Phospholipids in the cell membrane help regulate ion channels

Though the cell membrane is a protective barrier, it also plays a role in letting some foreign material in — via ion channels that dot the cell’s surface. Now new research from the Nobel Prize-winning laboratory that first solved the atomic structure of several such channels shows that their function is controlled in part by a complex interaction between a channel’s voltage sensor and the cell membrane immediately adjacent to it.

The cell membrane is a specialized environment, home to a variety of proteins that enable the cell to interact with its environment. One specific family of proteins, voltage-gated channels, are especially important in conducting signals along and between nerve cells. By opening when they sense a change in the electrical field surrounding a cell, these voltage-gated channels cause ions to rush in or out of the cell, conveying messages from adjacent cells.

It’s gating charges, made up of the positively charged amino acid arginine, that keep tabs on the electrical environment at the cell’s surface and thereby control when and for how long the pore remains open. Rockefeller University’s Roderick MacKinnon, who first published the structure of a voltage-gated potassium channel, known as KvAP, three years ago, has found that the channel’s function is also controlled by lipids in the cell membrane.

“The channel proteins are surrounded by lipids,” says Qiu-Xing Jiang, a postdoc in MacKinnon’s lab and co-first author. “We couldn’t help thinking, since you have positively charged arginines in the regulatory domains of the channels next to negatively charged phosphates in the heads of the phospholipids in the membrane, wouldn’t they form a really nice bonding pair? So the immediate question was whether the lipids were interacting at all with the channel proteins.”

Jiang, along with Daniel Schmidt, co-first author and a graduate student in the MacKinnon lab, made bilayers with non-phospholipids that were either positively charged, negatively charged, or had no charge at all. They then added KvAP channels and tested their function. “In each case, KvAP wouldn’t function,” says Schmidt.

Jiang and Schmidt then started adding back phospholipids to their membranes, and the channel started to function again. Then, as they began to dilute out the phospholipids, the channel became less and less functional. “The experiments all showed that it was the phosphate that made the difference. As long as it is there, the channel will work,” says Schmidt.

Further tests are needed to show whether this effect is due to a direct interaction between the positively charged arginine residues and the phosphate. “This work shows that the phospholipid membrane provides a stabilizing environment for the potassium channel,” says MacKinnon, a Howard Hughes Medical Institute investigator and the head of Rockefeller's Laboratory of Molecular Neurobiology and Biophysics. “The use of the arginine amino acids in voltage sensors may be an adaptation to the presence of phospholipids in cell membranes, and shows that the lipid composition of a cell membrane can offer additional levels of control and regulation to ion channels.”

This article was written from a news release by Rockefeller University.